Author + information
- S073510971634791X-26e5b36fc771e9f6821f3f0b93ef3a72Sabrina Nordin, MBBS,
- S073510971634791X-39a2d576bc7b9c0a3fc27d5dc19bde84Rebecca Kozor, MBBS,
- S073510971634791X-b6144efcd714d95ca8816c158f3cbdc8Heerajnarain Bulluck, MBBS,
- S073510971634791X-d6d7fcb7c150e36f1520d99f47a2c6afSilvia Castelletti, MD,
- S073510971634791X-6bf6c904a0ee8d9b751b703b0ae6c365Stefania Rosmini, MD,
- S073510971634791X-349bf87967aac094b1c876a5e41f6aabAmna Abdel-Gadir, MBBS,
- S073510971634791X-8c4508da756f1d9bcd7984d64b0d5e95Shanat Baig, MBBS,
- S073510971634791X-f5e4a3d9a09665a2d478342463b5ec7bAtul Mehta, PhD,
- S073510971634791X-a1212b73a90c9e996f6013bcf9716859Derralynn Hughes, PhD and
- S073510971634791X-13ae8ccda3a140646397d0ed10af7f3eJames C. Moon, MD∗ ()
- ↵∗Barts Heart Centre, St Bartholomew’s Hospital, West Smithfield, London EC1A 7BE, United Kingdom
Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by mutations in α-galactosidase A. Sphingolipid accumulates in organs including the heart, causing left ventricular hypertrophy (LVH) and myocardial fibrosis. Cardiac involvement is the leading cause of death in FD. Cardiovascular magnetic resonance (CMR) provides insights with late gadolinium enhancement (LGE) characteristically occurring in the basal inferolateral (BIFL) wall (1). Histological correlation in advanced disease indicates that this is focal fibrosis, although hybrid imaging with positron emission tomography/magnetic resonance has suggested this could be inflammation (2).
CMR can now measure 3 magnetic tissue properties (T1, T2, T2*) and display them as color maps. T1 is low in FD due to sphingolipid accumulation (3). However, the link between storage and LGE remains obscure. T2 mapping is sensitive to inflammation and edema in acute myocardial infarction and myocarditis (4,5). We hypothesized that inflammation contributes to LGE in FD, and is measurable using T2 mapping and troponin.
This is a single-center, single time point study using CMR and blood biomarkers in FD (n = 47, all gene positive, men and women) versus hypertrophic cardiomyopathy (HCM) (n = 28, gene-positive, asymmetrical LVH with LGE), chronic myocardial infarction (cMI) (n = 30, 6 months post-reperfused ST-segment elevation myocardial infarction) and normal controls (n = 60). Ethical approval was obtained. All participants underwent CMR, performed at 1.5-T (Avanto, Siemens Healthcare, Erlangen, Germany). T1 (Modified Look-Locker inversion recovery, 5s(3s)3s sampling) and T2 (WIP 448B, Siemens Healthcare) mapping were acquired on pre-contrast images. Conventional 2-dimensional LGE was acquired with phase sensitive inversion recovery. High-sensitivity troponin T was measured in FD.
Seven FD cases did not receive gadolinium due to patient preference. Of the remaining cases, 18 had LGE (14 of 21 men, all LVH positive; 4 of 19 women, 3 LVH positive), all in the BIFL wall, 8 with additional LGE elsewhere. The median LGE extent was 18 g (25th percentile: 12 g, 75th percentile: 24 g).
T1 in the remote myocardium in FD was lower than in HCM, cMI, and controls (934 ± 61 ms vs. 1,021 ± 40 ms, 1,003 ± 41 ms, 1,015 ± 36 ms; p < 0.001). T1 was elevated in LGE areas in all diseases but with lesser elevation in FD compared to HCM and cMI (1,096 ± 93 ms, 1,180 ± 66 ms, and 1,138 ± 52 ms, respectively; p < 0.05). However, the increase over remote T1 was higher in FD (204 ± 90 ms, 158 ± 62 ms, and 135 ± 57 ms, respectively; p < 0.05).
Remote area T2 was normal in all groups (51 ± 3 ms, 51 ± 3 ms, and 48 ± 2 ms, respectively, and controls 49 ± 2 ms). However, LGE T2 was very high in FD compared to HCM and cMI (64 ± 7 ms, 55 ± 4 ms, and 54 ± 3 ms, respectively; p < 0.001) (Figure 1) and higher than normal in every FD case (range 55 to 81 ms). The BIFL T2 was normal in cases without LGE, although slightly higher than controls (51 ± 3 ms vs. 49 ± 2 ms; p = 0.006).
Of the FD patients, 89% had troponin measured, of which 40% were elevated (median troponin 10 ng/l; 25th percentile: 1 ng/l, 75th percentile: 32 ng/l; range 3 to 93 ng/l; normal reference 0 to 14 ng/l). Troponin elevation only occurred when there was LGE (83% vs. 0%; p < 0.001) and was strongly LVH related (94% vs. 4%; p < 0.001). T2 in the BIFL wall correlated with log troponin (rs = 0.82; p < 0.001) and LV mass (rs = 0.69; p < 0.001) but not LGE extent (rs = 0.42; p = 0.08). In multivariate analysis, the strongest predictor of troponin was T2 in the BIFL wall (B = 2.4; p < 0.001).
We believe that the best explanation of these results—which combine blood and imaging biomarkers—is that LGE in the BIFL wall is not scar, but inflammation, supporting the former positron emission tomography/magnetic resonance data. Given that sampling was at a single (random) time point, the inflammation would appear chronic, suggesting FD with LGE is not only a storage disease but also a chronic inflammatory cardiomyopathy. Inflammation may be the pathological link in phenotype development—a concept that opens new avenues of therapy. Both blood troponin levels and T2 mapping are potential biomarkers for monitoring candidate therapies and risk stratification. We suspect that inflammation plays a wider role in cardiomyopathies, and that T2 and troponin should be further researched in FD and other diseases. Limitations of our study include no histological validation, and no other additional inflammatory markers.
Please note: This study was funded by an investigator-led research grant from Genzyme. Genzyme had no role in the study beyond the initial funding. Dr. Kozor was sponsored by Heart Research Australia (Sydney, Australia). Dr. Baig has received funding in part from a grant from Genzyme. Dr. Hughes has received honoraria for speaking and advisory board membership as well as support for research and travel from Shire, Genzyme, Sanofi, Amicus, and Protalix. Dr. Moon is funded indirectly by both the Biomedical Research Unit/Centres at Barts and University College London Hospitals. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Nordin and Kozor contributed equally to this work.
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